Tobacco addiction represents the most important preventable cause of illness and death in our society, responsible for more than 400,000 deaths each year. Currently, one out of five Americans smoke cigarettes, representing almost 50 million smokers in the United States alone. Half of all smokers will die of diseases directly related to tobacco use, and many smokers will suffer significant morbidity. Approximately 15 million smokers try to quit, but only one million of those succeed in smoking cessation each year.
A. Nicotine Addiction and Nicotine Addiction Therapy
A great deal of evidence supports the view that people continue to smoke because of the reinforcing effects of nicotine. Relevant findings include the fact that when allowed to control the nicotine content of each puff, smokers previously deprived of cigarettes, or administered a centrally acting nicotine antagonist, select higher nicotine concentrations. Moreover, under certain conditions, smokers, as well as animals, will self-administer intravenous nicotine.
The rewarding psychopharmacologic effects of nicotine are diverse. They include tranquilization, weight loss, decreased irritability, reduction in craving for cigarettes and other tobacco products, increased alertness, and improved cognitive function. These effects involve to some extent relief of withdrawal symptoms, which could be considered negative reinforcement by nicotine. However, some effects (e.g., improved attentiveness) have been demonstrated in non-dependent animals (Rose, 1996 Rev. Med. 47: 493).
Nicotine that is inhaled in tobacco smoke is rapidly absorbed and enters the pulmonary circulation, reaching the brain within several seconds. One cigarette provides 5-30 ng/ml of nicotine in venous blood (Rose, 1996). Nicotine has a metabolic half-life of roughly 2 hours, and cotinine is the main metabolite, Other mechanisms of nicotine delivery, such as snuff, and smoking pipes and cigars create the same effects once in the blood stream.
Nicotine is a powerful psychoactive drug that activates the same brain pathway as cocaine, and other psychostimulants, producing drug associated tolerance and withdrawal effects. In smokers, nicotine's rapid onset of central nervous system action and short half-life cause tolerance to develop quickly and provide an optimal environment for the development of nicotine dependence.
Several pharmacotherapies have proven effective for smoking cessation. These include nicotine replacement therapies (NRTs). Such NRTs come in the form of gum, the transdermal patch, nasal spray, and inhaler. The first FDA-approved pharmaceutical to provide nicotine replacement was Nicorette.RTM. (nicotine polacrilex), a chewing gum formulation that contained 2 mg, and later 4 mg, of nicotine in each piece. The gum delivered nicotine through buccal absorption following chewing.
Non-nicotine pharmacologic therapies are a more recently developed method of treating nicotine addiction. Possible reagents include nicotine blockade therapy, drugs affecting serotonergic neurotransmission, anti-depressants, anxiolytics, clonidine and airway sensory replacement (Rose, 1996; and Cinciripini et al., 1998 Oncology 12: 249-256). Nicotine blockade therapy (also referred to as nicotine receptor antagonists) utilizes compounds that occupy nicotine receptors, thereby attenuating the reward received from tobacco usage (Clarke, 1991 Br. J. Addict. 86: 501-505).
B. Anti-depressants and Anxiolytics
Anti-depressants have oftentimes been used to treat symptoms of nicotine withdrawal. One such anti-depressant is bupropion. Wellbutrin.RTM. is the trade name for the bupropion salt, bupropion HCl, an anti-depressant manufactured by Glaxo Wellcome. A sustained-release formulation of bupropion HCl, Wellbutrin SR.RTM., is also indicated for the treatment of depression. Glaxo Wellcome also has FDA approval to market a sustained release formulation of bupropion HCl as an aid to smoking cessation treatment for the smoking cessation indication. Glaxo Wellcome is marketing this product under the trade name Zyban.RTM.. Zyban.RTM. can be used either alone or in combination with a nicotine transdermal system (NTS). The mechanism of action of bupropion is unknown, but is thought to influence neurotransmitters. Specifically, bupropion is believed to operate on the neurochemistry of nicotine addiction by enhancing dopamine levels in the mesolimbic system and affecting noradrenergic neurons in the locus ceruleus portion of the brain. As dopamine had been associated with the rewarding effects of addictive substances, such as nicotine, inhibition of norepinephrine re-uptake was contemplated to induce a decrease of withdrawal symptoms (The Medical Letter 39: 77 (Aug. 15, 1997)).
Another anti-depressant successfully used in the treatment of smoking cessation is doxepin. Doxepin and pharmaceutically acceptable salts thereof were originally administered as anti-depressants (THE MERCK INDEX #3425: 539). Additional anti-depressants considered or utilized for smoking cessation treatment include imipramine (Nunn-Thompson et al., 1989 Clin. Pharm. 8: 710-720) and desipramine (Diana et al., 1990 Am. J. Physiol. 259: H1718-H1729).
Anxiolytics have also been administered to treat nicotine withdrawal. Anxiolytics counter the mild anxiety symptoms that occur during smoking cessation treatment, or the treatment of alcoholism or other substance abuse. The anxiolytic, isovaleramide, has been recommended for use in smoking cessation (Balandrin et al., WO 94/28888). Smoking cessation has also been treated with a combination of anti-depressants and anxiolytics (Glazer, U.S. Pat. No. 4,788,189)
C. Nicotine Receptor Antagonists
Another class of smoking cessation drugs are nicotine receptor antagonists, which are used to block the nicotinic receptor (Rose et al., 1997 Psychopharmacology 130: 28-40). Evidence suggests that smoking cessation may be facilitated by administration of a nicotinic antagonist having a selective action on central nicotinic cholinoceptors of the C6 (ganglionic) type (Clarke, 1987 Psychopharmacology 92: 135-143). Additional nicotinic receptors exist against which nicotine antagonists can operate. One nicotine receptor antagonist, mecamylamine and its pharmaceutically acceptable salts, has been explored as a possible pharmacotherapy for smoking cessation because it aids smoking cessation in both animals and humans (Tennant et al., 1984 NIDA Res. Monogr. 55: 291-297). Mecamylamine was patented in 1958 and since has been marketed as the anti-hypertensive agent, Inversine.RTM., which is mecamylamine hydrochloride (HCl) (Pfister, U.S. Pat. No. 2,831,027; THE MERCK INDEX #5654: 905). In the context of nicotine dependence, mecamylamine HCl has been shown to block many of the physiologic, behavioral, and reinforcing effects of nicotine.
Low doses of mecamylamine HCl have been shown to enhance smoking cessation when used in combination with a nicotine transdermal system (NTS) (Rose et al., 1994 Clin. Pharmacology & Therapeutics 56: 86; Levin et al., U.S. Pat. Nos. 5,574,052 and 5,316,759). In a double-blind clinical trial, in which nicotine was administered by skin patch treatment with or without concurrent mecamylarine (5 mg/bid), a threefold enhancement in continuous smoking abstinence rates was observed for the combined mecamylamine-nicotine patch group compared to the rate observed for the transdermal patch alone. Additionally, the therapeutic effect was sustained for the combined mecamylamine-nicotine patch group, whereas abstinence decreased four fold over 12 months in the NTS-only group. Another effect of the combined mecamylamine-NTS therapy was significantly reduced cravings for cigarettes, negative effect and appetite (Rose et al., 1994).
Thus, because drugs such as mecamylamine, or a pharmaceutically acceptable salt thereof, compete for the same receptor as nicotine, they have been beneficial in enhancing currently available smoking cessation therapies. Mecamylamine is a central and peripheral nicotine antagonist and causes individuals treated with mecamylamine to crave higher doses of nicotine than when the same individual is treated with agents which are peripheral nicotine antagonists only (e.g., trimethaphan) (Perkins et al., "Effects of Central and Peripheral Nicotinic Blockage on Human Nicotine Discrimination," Psychopharm. In press). Mecamylamine blocks the stimulus effects of both cytisine and nicotine, both of which bind to neuronal nicotinic receptors (Chandler et al., 1997 Psychopharmacology 129: 257-264).
Additional nicotinic antagonists include hexamethonium (Wotring et al., 1995 Neuroscience 67: 293-300), dihydro-beta-erythroidine (Stolerman et al., 1997 Psychopharmacology 129: 390-397), d-tubocurarine (Wotring et al., 1995), pempidine (Rapier et al., 1990 J. Neurochem. 54: 937-945), chlorisondamine (Caggiula et al., 1995 Psychopharmacology 122: 301-306), erysodine (Decker et al., 1995 Eur. J. Pharmacol. 280: 79-80) and trimethaphan camsylate (Hisayama et al., 1988 Br. J. Pharmacol. 95:465-472).
Some nicotinic antagonists have been combined with other agents to examine the effects on mean arterial pressure and renal sympathetic nerve activity. Two nicotinic receptor antagonists, pentolinium and hexamethonium, have been examined in combination with benextramine, desipramine and prazosin for their ability to modulate blood pressure (Martin 1997 J. Auton. Pharmacol. 17: 249-259). However, combinations of nicotinic antagonists and either anti-depressants or anxiolytics have not been previously indicated for use in the treatment of smoking cessation or for other substance addiction therapies.
D. Treatment of Cocaine Addiction
Cocaine addiction has been treated with some of the drugs used for smoking cessation as a means of decreasing cocaine withdrawal symptoms. For example pharmacotherapy with desipramine, amantadine and bromocriptine was shown in preliminary studies to minimize the symptoms of cocaine withdrawal (Hall et al., 1990 Pharmacotherapy 10: 47-65; and Kosten et al., 1991 NIDA Res. Monogr. 105: 510-511).
Combinations of desipramine and amantadine have facilitated greater opiate and cocaine abstinence (Oliveto et al., 1995 J. Subst. Abuse Treat. 12: 423-428).